Imp7 siRNA nanoparticles protect against mechanical ventilation-associated liver injury by inhibiting HMGB1 production and NETs formation

Mechanical ventilation (MV) has the potential to induce extra -pulmonary organ damage by adversely affecting the lungs and promoting the secretion of inflammatory cytokines. High -mobility group box 1 protein (HMGB1) is a pro -inflammatory mediator in ventilator -induced lung injury (VILI), but its effect on MV -associated liver injury and the mechanisms are poorly understood. In the present study, mice were subjected to high -volume MV (20 ml/kg) to induce VILI. MV -induced HMGB1 prompted neutrophil extracellular traps (NETs) formation and PANoptosis within the liver. Inhibiting NETs formation by DNase I or PAD4 inhibitor, or by HMGB1 neutralizing ameliorated the liver injury. HMGB1 activated neutrophils to form NETs through TLR4/MyD88/TRAF6 pathway. Importantly, Importin7 siRNA nanoparticles inhibited HMGB1 release and protected against MV -associated liver injury. These data provide evidence of MV -induced HMGB1 prompted NETs formation and PANoptosis in the liver via the TLR4/MyD88/TRAF6 pathway. HMGB1 is a potential therapeutic target for MV -associated liver injury.